Optically active imidazolidinone derivatives and processes for preparing them

ABSTRACT

PCT No. PCT/JP94/01505 Sec. 371 Date Mar. 15, 1996 Sec. 102(e) Date Mar. 15, 1996 PCT Filed Sep. 12, 1994 PCT Pub. No. WO95/07905 PCT Pub. Date Mar. 23, 1995An optically active imidazolidinone derivative represented by general formula (1), having a cholinergic activity (a muscarine M1 activity) and being useful for treating senile dementia, a pharmacologically acceptable acid-addition salt thereof, and a process for producing the same, wherein R and R1 may be the same or different and each represents hydrogen, halogen, optionally halogenated lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, nitro, amino or cyano; and n represents 1 to 4.

SPECIFICATION

This application is a 371 of PCT/JP94/01505 filed Sep. 12, 1994.

1. Technical Field

The present invention relates to optically active imidazolidinonederivatives with cholinergic activity (muscarine M₁ activity) orpharmaceutically acceptable acid addition salts, processes for preparingthem and therapeutic drugs for senile dementia having them as effectivecomponents.

2. Background Techniques

In recent years, as the average span of life becomes long, the seniledementia such as Alzheimer type senile dementia has posed a significantproblem both medically and socially.

The patients of dementia show symptom such as loss of intellectualability, disturbance of memory, disturbance of abstract thinking, verbalaphasia, apraxia, disorientation, etc. and the disorder of basicfunctions lies in the disturbance of the formation of memory or theexpressive ability of retained memory. Until today, however, there havebeen almost no medicaments that can treat this effectively, henceimmediate development of therapeutic drugs is desired.

It is said that the disturbances of learning and memory in the patientsof dementia (in particular, senile dementia and Arzheimer type seniledementia) are particularly associated with the decrease in centralcholinergic function. Hence, such compounds that have this centralcholinergic function, that is, the functional activity of acetylcholinebeing a nerve transmitter can be used for the treatment of patients ofdementia (Science, 217, 408 (1982): R. I. Bartus et al.).

It is said that, among the degenerative diseases of nerve due todecreased central cholinergic function, the core symptoms relatingparticularly to the disturbances of memory, recognition, etc. are due tothe decreased function of central cholinergic nerve and conventionally,for improving these core symptoms, administration ofacetylcholinesterase inhibitor such as physostigmine, administration ofacetylcholine precursors such as choline and lecithin, administration ofdrugs acting on the cholinergic receptor such as arecoline, and the likehave been attempted (e.g. Dementia, 1, 188 (1987) etc.). All of theseattempts however have many problematic points that they are ineffectivein the therapy, that, even if slight effect may be developed, adverseeffect is strong or the therapeutic range is narrow, and the like.

Moreover, the optically active imidazolidinone derivatives of theinvention are not described in the literatures, but, for compoundsrelat.ing to racemic form, there is U.S. Pat. No. 3,459,757 (Aug. 5,1969) showing a following general formula. ##STR1## (wherein R and R¹denote hydrogen atoms, halogen atoms, lower alkyl groups, lower alkoxygroups or trifluoromethyl groups, A and B denote hydrogen atoms or loweralkyl groups, Y denotes an oxygen atom or sulfur atom, m denotes 0 to 1,and n denotes 0 to 2).

In this patent, however, a description that the compounds are effectivefor the CNS depressant properties, muscle relaxant, etc. at a level ofnontoxicity can be found, but there is no description at all that theyhave muscarine (M₁) activity.

In addition, a compound represented by a following formula ##STR2## isdescribed in the example, but this compound is of racemic form and thereis no sign at all that it was developed as a medicinal drug.

The purpose of the invention is to provide the therapeutic drugs forsenile dementia which activate the central cholinergic function of thepatients of dementia (in particular, senile dementia and Arzheimer typesenile dementia) and which are effective for the therapy of thedisturbance of memory and having high safety, taking the present statusof the patients of dementia aforementioned into consideration.

DISCLOSURE OF THE INVENTION

As a result of diligent studies searching for the therapeuticsarticularly for the disturbance of memory among various symptoms ofdementia for the purpose of developing novel therapeutics for seniledementia, the inventors have found that the inventive optically activeimidazolidinone derivatives and their acid adducts have excellentcholinergic activity (muscarine M₁ activity).

Namely, according to the invention, it has been found that theimidazolidinone derivatives represented by a general formula (1)##STR3## (wherein R and R¹ denote identically or differently hydrogenatoms, halogen atoms, lower alkyl groups which may be substituted byhalogen atom, lower alkoxy groups, lower alkylthio groups, loweralkoxycarbonyl groups, nitro groups, amino groups or cyano groups, and ndenotes 1 to 4), or their acid adducts have surprisingly excellentcholinergic activity (muscarine M₁ activity), leading to the completionof the invention.

Comparing the effect of drugs of the inventive compounds (R form) withthat of corresponding racemic form and antipode (S form), as describedlater, it was found that, in the in vitro muscarine (M₁) activity, Rform had about 120 times as excellent as activity over S form and about3 times over racemic form and additionally that the in vivo improvingaction on the disturbance of learning could be recognized only for Rform with significant difference.

Moreover, from clinical impressions, common symptoms i.e. convulsiveactions were seen in the administration groups of racemic form and Sform, and further, with regard to the toxicity, even at a dose that allcases (4/4) brought about death in the administration group of racemicform, that is, even at 1200 mg/kg p.o., problems did not arise at anyrate in the administration group of R form. Based on this fact, it wasmade clear that undesirable actions with racemic form (convulsive commonsymptoms and toxicity) depended on the S form.

The optically active imidazolidinone derivatives (R form) in theinvention, therefore, are therapeutic drugs for senile dementia whichactivate the central cholinergic function of the patients of dementia(in particular, senile dementia and Arzheimer type senile dementia) andwhich are effective for the therapy of the disturbance of memory andhaving high safety.

In the description of the general formula (1) of the invention, for"lower alkyl", straight chain or branched ones with carbon atoms of 1 to6 such as methyl, ethyl, n-propyl and isopropyl are mentioned.

For "halogen atom", fluorine, chlorine, bromine and iodine arementioned, for "lower alkoxy", straight chain or branched ones withcarbon atoms of 1 to 4 such as methoxy, ethoxy and propoxy arementioned, for "lower alkoxycarbonyl group", methoxycarbonyl,ethoxycarbonyl, etc. are mentioned, and "amino group" may be substitutedby acyls, for example, acetyl etc. or may be substituted by one or twolower alkyl groups. For "protective group of amino group", for example,lower acyl groups such as acetyl and propionyl, lower alkoxycarbonylgroups such as ethoxycarbonyl and tert-butoxycarbonyl, and benzyl groupare mentioned.

For "eliminating group", for example, halogen atoms such as fluorine,chlorine, bromine and iodine, and sulfonyloxy groups such asp-toluenesulfonyloxy group and methanesulfonyloxy group are mentioned.

"Acid addition salts" are pharmaceutically acceptable salts with, forexample, hydrochloric acid, citric acid, succinic acid, fumaric acid,maleic acid, etc.

The inventive compounds represented Dy the general formula (1) can beprepared through, for example, four kinds of preparative processes shownbelow ( A! through D!).

A!The compounds represented by the general formula (1) can besynthesized by submitting compounds represented by a general formula (2)##STR4## (R,R¹ and n are as described above), to carbonyl-insertionreaction, for example, by reacting for 1 to 5 hours at 0° to 150° C. ina suitable solvent such as tetrahydrofuran, dioxane, benzene,acetonitrile or chloroform or without solvent, using a cyclizing agentsuch as N,N'-carbonyldiimidazole, phosgene or diethyl carbonate.

The compounds represented by the general formula (2) can be synthesizedaccording to following scheme. ##STR5## (R,R¹ and n are as describedabove).

Namely, they can be synthesized in a way that optically active3-amino-1-aralkyl piperidine (8) is reacted with a suitableN-phenylglycine (9) for 1 to 7 hours at 0° to 25° C. in a suitablesolvent such as tetrahydrofuran, N,N-dimethylformamide, benzene,acetonitrile, dichloromethane or chloroform in the presence of asuitable base such as triethylamine, pyridine orN,N-dimethylaminopyridine, using a condensing agent such asN,N'-dicyclohexylcarbodiimide (DCC), diethyl phosphoryl cyanide (DEPC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) orchloroformic ester (acid anhydride process) to give amide form (10), andthis is reacted for 1 to 10 hours at 20° C. to boiling point of solventin a suitable solvent such as ether, tetrahydrofuran, dioxane or benzenein the presence of a reducing agent such as lithium aluminumhydride orborane complex (e.g. borane-tetrahydrofuran complex etc.).

Moreover, they can also be synthesized by reacting optically active3-amino-1-aralkylpiperidine (8) with corresponding aldehyde form (11)for 2 to 6 hours at 20° C. to boiling point of solvent in a suitablesolvent such as toluene or xylene in the presence of a reducing agentsuch as sodium borohydride or sodium cyanoborohydride.

The compounds represented by the general formulae (9) and (11) referredto so here are publicly known and can be synthesized according to, forexample, Japan Patent Kokai No. Sho 57-116003, J. Med. Chem., 8, 405(1965), J. Chem. Soc., 307 (1949), J. Org.. Chem., 23, 186 (1958),German Patent No. DE 3,300,004, etc.

B! The compounds represented by the general formula (1) can also besynthesized by reacting compounds represented by a general formula (3)##STR6## (wherein R,R¹ and n are as described above, and R³ denotes ahydrogen atom, lower alkyl group or aralkyl group), for 2 to 10 hours at90° to 150° C. in an acid such as hydrobromic acid or hydrochloric acidor a halogenating agent such as thionyl chloride or phosphorustribromide.

The compounds represented by the general formula (3) can be synthesizedaccording to following scheme. ##STR7## (Z denotes a hydroxyl group orhalogen atom, and R,R¹,R³ and n are as described above).

Namely, they can be synthesized in a way that optically active3-amino-1-aralkylpiperidine (8) is reacted with corresponding carboxylicacid form or its acid halide (12) for 2 to 5 hours at 0° to 25° C. in asuitable solvent such as tetrahydrofuran, benzene, dichloromethane orchloroform in the presence of a condensing agent such asN,N'-dicyclohexylcarbodiimide (DCC), diethyl phosphoryl cyanide (DEPC)or 1-(3-dimethylamiopropyl)-3-ethylcrbodiimide hydrochloride (EDCI)(acid anhydride process using chloroformic ester may also be possible)or in the presence of a suitable base such as triethylamine or pyridineto give amide form (13), this is reacted for 1 to 10 hours at 0° C. toboiling point of solvent in a suitable solvent such as tetrahydrofuran,ether, dioxane or benzene in the presence of a reducing agent such aslithium aluminum hydride or borane complex (e.g. borane-tetrahydrofurancomplex etc.) to convert to amine form (14), and this is reacted with asuitable isocyanic ester (15) in a suitable solvent such astetrahydrofuran, benzene, dichloromethane, chloroform orN,N-dimethylformamide or without solvent in the presence of a suitablebase such as triethylamine or pyridine.

The compounds represented by the general formula (8), that is, opticallyactive 3-amino-1-aralkylpiperidines (8) are novel compounds and can besynthesized according to following scheme. ##STR8## (R and n are asdescribed above, and X denotes an eliminating group).

Namely, (R)-ethyl nipecotate (27) obtained through optical resolution bya published method, a method described in Recueil. Tray. chim. Pays-Bas.70, 899 (1951), Chem. Ber., 102, 2864 (1969), is reacted with aqueousammonia for 2 to 4 days at 0° to 30° C. to give nipecotamido (28), andthis can be converted to amide form (29) by reacting with aralkyl form(5) for 2 to 10 hours at 0° to 20° C. in a suitable solvent such astetrahydrofuran, acetonitrile, dichloromethane or ethanol or in amixture thereof in the presence of a suitable base such astriethylamine, pyridine or N,N-dimethylaminopyridine.

By conducting retention of configuration reaction such as Hofmannrearrangement reaction on the amide form (29) obtained here, opticallyactive 3-amino-1-aralkylpiperidine (8) can be synthesized.

C! The compounds represented by the general formula (1) can also besynthesized by reacting compounds represented by a general formula (4)##STR9## (wherein R¹ is as describe above), with compounds representedby a general formula (5) ##STR10## (wherein R, X and n are as describedabove), for 2 to 10 hours at 25° to 100° C. in a suitable solvent suchas tetrahydrofuran, acetonitrile, dichloromethane or ethanol or mixturethereof in the presence of a suitable base such as potassium carbonate,triethylamine, pyridine or N,N-dimethylaminopyridine.

The compounds represented by the general formula (4) can be synthesizedby deprotecting compounds represented by a general formula (19)##STR11## (wherein R¹ is as-described above, and R² denotes a protectivegroup of amino group), for example, by reacting for 1 to 7 hours at 20°to 120° C. in a suitable solvent such as tetrahydrofuran or ethanol orwithout solvent in the presence of an acid such as hydrochloric acid orhydrobromic acid.

Moreover, in the case of R² being a benzyl group, they can besynthesized through catalytic hydrogenation. Namely, they can besynthesized by reacting for 1 to 5 hours at 20° to 100° C. under anapplied hydrogen pressure of 50 to 70 kg/cm³ in a suitable solvent suchas methanol, ethanol or acetic acid in the presence of a catalyst suchas palladium carbon (Pd-C), platinum carbon (Pt-C), rhodium carbon(Rh-C), platinum oxide (PtO₂) or rhodium alumina (Rh-Al₂ O₃), or byreacting together with stoichiometric ammonium formate for 2 to 10 hoursat 20° C. to boiling point of solvent in a suitable solvent such asmethanol, ethanol or water or a mixed solvent thereof in the presence ofa catalyst such as palladium carbon (Pd-C), platinum carbon (Pt-C),rhodium carbon (Rh-C), platinum oxide (PtO₂) or rhodium alumina (Rh-Al₂O₃).

The compounds represented by the general formula (19) can be synthesizedaccording to following scheme (I, II or III). ##STR12## (R¹ and R² areas described above.)

Namely, they can be synthesized in a way that optically active3-aminopiperidine (16) with amino group protected is reacted with asuitable N-phenylglycine (9) for 1 to 7 hours at 0° to 25° C. in asuitable solvent such as tetrahydrofuran, N,N-dimethylformamide,benzene, acetonitrile, dichloromethane or chloroform in the presence ofa suitable base such as triethylamine, pyridine orN,N-dimethylaminopyridine, using a suitable condensing agent such asN,N'-dicyclohexylcarbodiimide (DCC), diethyl phosphoryl cyanide (DEPC),1-(3-dimethylaminopropyl)-3-ethylcrbodiimide hydrohloride (EDCI) orchloroformic ester (acid anhydride process) to give amide form (17),this is reacted for 1 to 10 hours at 20° C. to boiling point of solventin a suitable solvent such as ether, tetrahydrofuran, dioxane or benzenein the presence of a reducing agent such as lithium aluminum hydride orborane complex (e.g. borane-tetrahydrofuran complex etc.), to convert toethylenediamine form (18), and this is submitted to carbonyl-insertionreaction, for example, by reacting for 1 to 5 hours at 0° to 150° C. ina suitable solvent such as tetrahydrofuran, dioxane, benzene,acetonitrile or chloroform or without solvent, using a cyclizing agentsuch as N,N'-cabonyldiimidazole, phosgene or diethyl carbonate.

Moreover, the ethylenediamine form (18) can also be synthesized byreacting optically active 3-aminopiperidine (16) with amino groupprotected with corresponding aldehyde form (11) for 2 to 6 hours at 20°C. to boiling point of solvent in a suitable solvent such as toluene orxylene in the presence of a reducing agent such as sodium borohydride orsodium cyanoborohydride. ##STR13## (Z denotes a hydroxyl group orhalogen atom, and R¹,R²,R³ and n are as described above).

Namely, they can be synthesized in a way that optically active3-aminopiperidine (16) with amino group protected is reacted withcorresponding carboxylic acid form or its acid halide (12) for 2 to 5hours at 0° to 25° C. in a suitable solvent such as tetrahydrofuran,benzene, dichloromethane or chloroform in the presence of condensingagent such as N,N'-dicyclohexylcarbodiimide (DCC), diethyl phosphorylcyanide (DEPC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride (EDCI) (acidanhydride process using chloroformic ester may also be possible) or inthe presence of a suitable base such as triethylamine or pyridine togive amide form (20), this is reacted for 1 to 10 hours at 0° C. toboiling point of solvent in a suitable solvent such as tetrahydrofuran,ether, dioxane or benzene in the presence of a reducing agent such aslithium aluminum hydride or borane complex (e.g. borane-tetrahydrofurancomplex etc.) to convert to amine form (21), this is reacted with asuitable isocyanic ester (15) in a suitable solvent such astetrahydrofuran, benzene, dichloromethane, chloroform orN,N-dimethylformamide or without solvent in the presence of a suitablebase such as triethylamine or pyridine to give urea form (22), then R³is selectively deprotected to give alcohol form (23), and this isreacted for 2 to 5 hours at 90° to 150° C. in a halogenating agent suchas thionyl chloride or phosphorus tribromide.

The compounds represented by the general formula (4) can also besynthesized through one process without passing through the generalformula (19) by reacting urea form (22) obtained as above for 2 to 5hour at 90° to 150° C. in an acid such as hydrobromic acid orhydrochloric acid. ##STR14## (wherein R¹ and R² are as described above,and X denotes an eliminating group).

Namely, they can also be synthesized in a way that optically active3-aminopiperidine (16) with amino group protected is reacted withchloroethyl isocyanate (24) for 1 to 10 hours at 25° to 80° C. in asuitable solvent such as tetrahydrofuran, acetonitrile,N,N-dimethylformamide or methylene chloride to give urea form (25), thisis intramolecular cyclized in the presence of a suitable base such assodium hydride to give compound (26), and this is reacted with compoundsof a general formula (7) in a suitable solvent such as tetrahydrofuran,acetonitrile or N,N-dimethylformamide, using a suitable base such assodium hydride or N,N-dimethylaminopyridine.

Moreover, the compounds represented by the general formula (16), thatis, optically active 3-aminopiperidines with amino group protected arealso novel compounds and can be synthesized according to followingscheme. ##STR15## (R² is as described above).

Namely, in the synthesis of said optically active3-amino-1-aralkylpiperidine (8), they can be synthesized by convertingto amide form (32) introduced with a protective group of amino group,for example, protective group (R²) using ethyl chloroformate in place ofreacting aralkyl form (5) with nipecotic amide (28), and by similarprocess using Hofmann rearrangement reaction. Further, optically active3-aminopiperidine (16) with amino group protected can also besynthesized by introducing a protective group to amino group ofoptically active ethyl nipecotate (27) to give compound (33),hydrolyzing this to convert to carboxylic acid form (34) or its acidchloride form (35), and conducting Curtius transition reaction.

D! The compounds represented by the general formula (1) can also besynthesized by reacting compounds represented by a general frmula (6)##STR16## (wherein R and n are as described above), with compoundsrepresented by a general formula (7) ##STR17## (wherein R¹ is asdescribed above, and X denotes an eliminating group), for 1 to 10 hoursat 25° to 80° C. in a suitable solvent such as tetrahydrofuran,acetonitrile or N,N-dimethylformamide, using a suitable base such assodium hydride.

The compounds represented by the general formula (6) can be synthesizedaccording to following scheme. ##STR18## (wherein R and n are asdescribed above).

Namely, they can be synthesized in a way that optically active3-amino-1-aralkylpiperidine (8) is reacted with chloroethyl isocyanate(24) for 1 to 10 hours at 25° to 80° C. in a suitable solvent such astetrahydrofuran, acetonitrile, N,N-dimethylformamide or methylenechloride to give urea form (30), and this is intramolecular cyclized inthe presence of a suitable base such as sodium hydride.

Moreover, the compounds represented by the general formula (1) andgeneral formula (4) and the compounds represented by the general formula(8) and general formula (16) can also be converted to optically activecompounds (1), (4), (8) and (16) by submitting their racemic formthemselves to optical resolution with optical resolving agent, forexample, dibenzoyltartaric acid or the like.

When pharmaceutically acceptable acid addition salts of the compoundsrepresented by the general formula (1) are required, they can beobtained by reacting synthesized imidazolidinone derivatives with, forexample, inorganic acids such as hydrochloric acid or organic acids suchas maleic acid.

Best embodiment for putting the invention into practice

The preparative examples and the examples of the invention will bedescribed to illustrate the invention in more detail.

(EXAMPLE 1) (R)-1-(4-florophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

To a 30 ml distilled tetrahydrofuran solution of 9.70 g (29.6 mmol) of(R)-N-4-florophenyl-N'-3-(1-phenylmethyl)-piperidylethylenediamine in a200 ml round-bottomed flask were added 9.61 g (2 eg.) ofN,N'-carbonyldiimidazole (CDI) at room temperature, and the mixture wasrefluxed for 1 hour under heat. Thereafter, solvent was distilled off at100° C. in an oil bath under atmospheric pressure to obtain the residue,which was heated for 1 hour at about 110° C. and allowed to stand for 2days. To this residue were added 200 ml of methylene chloride todissolve, and further 200 ml of water were added to extract and separatethe organic layer. The aqueous layer was made to be pH of 12 or higherwith 2N sodium hydroxide, which was extracted with methylene chloride(100 ml×2) These methplene chloride layers were combined with previouslyextracted layer, dried over anhydrous sodium sulfate, and then solventwas distilled off under reduced pressure to obtain a brown oil. This waspurified by column chromatography (silica gel, n-hexane:ethylacetate=3:5) and then recrystallized to obtain 3.56 g (yield 34 %) oftitle compound.

m.p. 122°-123° C. (2-propanol) colorless prisms α!_(D) ²⁵ =+11° (1=50 c.5.0 chloroform) Elemental analysis (%); As C₂₁ H₂₄ FN₃ O Calculated; C:71.36 H: 6.84 N: 11.89 Found; C: 71.56 H: 6.89 N: 11.81

The starting material,(R)-N-4-fluorophenyl-N'-3-(1-phenylmethyl)piperidylethylenediamine wassynthesized as follows:

(Referential Example 1)(R)-2-(N-4-fluorophenyl)amino-N'-3-(1-phenylmethyl) piperidylacetamide

To a 100 ml dried N,N'-dimethylformamide solution of 8.18 g (43.0 mmol)of (R)-1-phenylmethyl-3-aminopiperidine in a 200 ml round-bottomed flaskwere added 7.27 g (1 eg.) of N-4-fluorophenylglycine at roomtemperature. This was cooled to 10° C. and 6.87ml (1 eg.) of diethylphosphoryl cyanide (DEPC, 95 %) and 6 ml (1 eg.) of triethylamine wereadded dropwise in turn. After dropwise addition, the reaction mixturewas stirred for 2 hours at room temperature. After allowed to standovernight, the reaction mixture was distilled off under reduced pressureand 150 ml of water were added to the residue, which was stirred for 15minutes, then deposited oily product was separated. The separated oilyproduct was dissolved into 100 ml of methylene chloride and, afterwashed with saturated aqueous solution of sodium hydrogen carbonate andsaturated aqueous solution of sodium chloride in turn, the organic layerwas separated. The aqueous layer was extracted again with methylenechloride (100 ml×3). In addition, to the filtrate at the time of havingseparated the oily product were added 250 ml of water. This wasextracted with ethyl acetate (100 ml×2) and washed with saturatedaqueous solution of sodium chloride, then the organic layer wasseparated. Previous methylene chloride, then the organic layer wasseparated. Previous methylene chloride layer was combined with ethylacetate layer and, after dried over anhydrous sodium sulfate, solventwas distilled off under reduced pressure to obtain brown residue. Thiswas purified by column chromatography (silica gel, ethyl acetate) toobtain 13.3 g (yield 91%) of title compound as a brown oil.

α!_(D) ²⁵ =-15° (1=50, c. 5.0, chlorform) MASS; As C₂₀ H₂₄ FN₃ O m/e;341 (M⁺), 217, 173, 124, 91 (base)

(Referential Example 2)(R)-N-4-fluorophenyl-N'-3-(1-phenylmethyl)piperidyl ethylenediamine

To a 100 ml dioxane suspension of 5.14 g (3.5 eg.) of lithium aluminumhydride in a 500 ml round-bottomed flask was added dropwise a 180 mldioxane solution of 13.2 g (38.7 mmol) of(R)-2-(N-4-fluorophenyl)amino-N'-3-(1-phenylmethyl)-piperidylacetomideby portions at room temperature. After dropwise addition, the reactionmixture was returned to room temperature and it was stirred for 1 hourand further refluxed for 6 hours. After allowed to stand overnight, thereaction mixture was added carefully into about 200 ml of ice water andit was stirred for 30 minutes. Concentrated hydrochloric acid was addedto this to make pH 1 or higher, which was extracted with ethyl acetate(200 ml). The aqueous layer was separated and the organic layer wasextracted with 2N hydrochloric acid (200 ml×3). Combining these withprevious aqueous layer, pH was made to be 12 or higher using potassiumhydroxide under cooling with ice. After added with ethyl acetate (300ml) to this, the mixture was stirred for 30 minutes and further celitewas added to filter off. The filtrated residue was washed well withethyl acetate and the organic layer of liltrate was separated. Theaqueous layer was extracted with ethyl acetate (30 ml×3), which werecombined with previous organic layer. After dried over anhydrous sodiumsulfate, solvent was distilled off under reduced pressure to obtainbrown residue. This was purified by column chromatography (alumina,n-hexane:ethyl acetate=2:5) to obtain 9.70 g (yield 77 %) of titlecompound as a brown oil.

α!_(D) ²⁵ =-9.2° (1=50, c. 8.7, ethyl acetate) 1H-NMR (TMS in CDCl₃,90MHz) δ. 1.15-2.28 (6H, m), 2.42-2.94 (5H, m), 2.97-3.23 (2H, m), 3.49(2H, s), 6.45-6.61 (2H, m), 6.77-6.97 (2H, m), 7.28 (5H, s)

(EXAMPLE 2) (R)-1-(4-chlorophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

By the similar method to Example 1, title compound was synthesized.

m.p. 158°-160° C. (ethyl acetate: n-hexane) colorless prisms α!_(D) ²⁶=+15° (1=50, c. 3.0, chloroform) Elemental analysis (%); As C₂₁ H₂₄ ClN₃O Calculated; C: 68.19 H: 6.54 N: 11.36 Found; C: 68.23 H: 6.64 N: 11.41

The starting material,(R)-N-4-chlorophenyl-N'-3-(1-phenylmethyl)piperidylethylenediamine wassynthesized as follows:

(Referential Example 3)(R)-2-(N-4-chlorophenyl)amino-N'-3-(1-phenylmethyl)-piperidylacetamide

By the similar method to Referential example 1, title compound wassynthesized.

α!_(D) ²⁸ =-19° (1=50, c. 4 9, chloroform) MASS; As C₂₀ H₂₄ ClN₃ O m/e;357 (M⁺), 217, 173, 91 (base)

(Referential Example 4)(R)-N-4-chlorophenyl-N'-3-(1-phenylmethyl)piperidyl-ethylenediamine

By the similar method to Referential example 2, title compound wassynthesized.

α!_(D) ²⁷ =-8.4° (1=50, c. 8.6, ethyl acetate) ¹ H-NMR (TMS in CDCl₃,90MHz) δ. 1.05-2.27 (7H, m), 2.39-2.87 (5H, m), 2.93-3.21 (2H, m), 3.48(2H, s), 6.51 (2H, d, J=9.2 Hz), 7.08 (2H, d, J=8.8Hz), 7.27 (5H, s)

Optically active (R)-1-phenylmethyl-3-aminopiperidine was synthesized asfollows:

(Referential Example 5) (R)-ethyl nipecotate

From (±)-ethyl nipecotate, (R)-ethyl nipecotte (L)-tartrate wassynthesized as colorless plates according to the method described inRecueil. Tray. chim. Pays-Bas., 70, 899 (1951).

m.p. 154°-155° C. (ethanol) α!_(D) ²⁵ =+53° (1=50, c. 2.0, 0.2 %ammonium molybdate)

Further, the tartrate obtained was hydrolyzed by the similar method tosynthesize title compound as a slightly yellowish brown oil.

b.p. 110°-120° C./0.5 mmHg α!_(D) ²⁸ =-1.1° (1=50, c. 9.9, water) MASS;As C₈ H₁₅ NO₂ m/e; 157 (M⁺), 128, 112, 84 (base)

(Referential Example 6) (R)-3-(1-phenylmethyl)nipecotamido

To 14.7 g (93.5 mmol) of (R)-ethyl nipecotate in a 300 ml round-bottomedflask were added 200 ml of concentrated aqueous ammonia at roomtemperature, and the mixture was allowed to stand for 3 days at roomtemperature. The reaction mixture was distilled off at a water bathtemperature of lower than 40° C. to obtain (R)-nipecotamide as a paleyellow oil. To this were added 100 ml of methylene chloride and 50 ml ofethanol at room temperature, and 15.6 ml (1.2 eg.) of triethylamine wereadded while cooling with ice. To this reaction mixture were graduallyadded dropwise 11.1 ml (1 eg.) of benzyl bromide under cooling with ice.After dropwise addition, the mixture was stirred for 10 minutes undercooling with ice and further for 4 hours after returned to roomtemperature, which was allowed to stand overnight. The reaction mixturewas distilled off under reduced pressure and the residue obtained wasdissolved into 200 ml of methylene chloride, which was washed with 1Nsodium hydroxide and saturated aqueous solution of sodium chloride inturn. The aqueous layer was extracted with methylene chloride (50 ml×3)and, after washed with saturated aqueous solution of sodium chloride,these were combined with previous organic layer and dried over anhydroussodium sulfate. Solvent was distilled off under reduced pressure and theresidue thus obtained was recrystallized to obtain 8.61 g (yield 42 %)of title compound.

m.p. 112°-113° C. (acetonitrile) colorless prisms α!_(D) ²⁶ =-18° (1=50,c. 10, ethanol) MASS; C₁₃ H₁₈ N₂ O m/e; 218 (M⁺), 174, 127, 91 (base)

(Referential Example 7) (R)-1-phenylmethyl-3-aminopiperidine

A 120 ml aqueous solution of 16.8 g (8.2 eg.) of sodium hydroxide in a500 ml round-bottomed flask was cooled with ice and to this was added a120 ml dioxane solution of 11.2 g (51.3 mmol) of(R)-3-(1-phenylmethyl)nipecotamido, followed by dropwise addition of3.28 ml (1.24 eg.) of bromine. After dropwise addition, the reactionmixture was reacted for 35 minutes at 65° to 70° C. After allowed tostand overnight, the organic layer was separated. The aqueous layer wasextracted with ethyl acetate (100 ml×3), which were combined withprevious organic layer. After dried over anhydrous sodium sulfate,solvent was distilled off under reduced pressure to obtain pale yellowresidue. This was distilled under reduced pressure to obtain 8.18 g(yield 84 %) of title compound.

b.p. 200°-220° C./0.5 mmHg α!_(D) ²² =-13° (1=50, c. 10, ethanol) ¹H-NMR (TMS in CDCl₃, 90MHz) δ. 0.84-1.26 (1H, m), 1.26 (2H, s),1.42-2.18 (5H, m), 2.42-3.00 (3H, m), 3.48 (2H, s), 7.28 (SH, s)

(Referential Example 8) (±)-1-(4-fluorophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

Using (±)-1-phenylmethyl-3-aminopiperidine as a stating material, titlecompound was synthesized similarly to Referential examples 1 and 2 andExample 1.

The starting material, (±)-1-phenylmethyl-3-aminopiperidine wassynthesized from (±)-ethyl nipecotate similarly to Referential examples6 and 7.

m.p. 118°-119° C. (2-prepanol-n-hexane) colorless prisms Elementalanalysis (%); As C₂₁ H₂₄ FN₃ O Calculated; C: 71.36 H: 6.84 N: 11.89Found; C: 71.56 H: 6.89 N: 11.89

(Referential Example 9) (S)-1-(4-fluorophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

Using (S)-1-phenylmethyl-3-aminopiperidine as a starting material, titlecompound was synthesized similarly to Referential examples 1 and 2 andExample 1.

The starting material, (S)-1-phenylmethyl-3-aminopiperidine wassynthesized similarly to referential examples 6 and 7, after (s)-ethylnipecotate from (±)-ethyl nipecotate was synthesized by the methoddescribed in Recueil. Travl. chim. Pays-Bas, 70, 899 (1951).

m.p. 121.5°-122.5° C. (2-propanol) colorless prisms α!_(D) ²⁶ =-11°(1=50, c 4.9, CHCl₃) Elemental analysis (%); As C₂₁ H₂₄ FN₃ OCalculated; C: 71.36 H: 6.84 N: 11.89 Found; C: 71.47 H: 6.88 N: 11.69

(EXAMPLE 3) (R)-1-(3,4-dimethoxyphenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

To a 30 ml anhydrous tetrahydrofuran solution of 3.02 g (8.17 mmoi) of(R)-N-3,4-dimethoxyphenyI-N'-3-(1-phenylmethyl)piperidylethylenediaminein a 200 ml rounmd-bottomed flask were added 2.65 g (2 eg.) ofN,N'-carbonyldiimidazole (CDI) at room temperature, and the mixture wasrefluxed for 2 hours. Thereafter, solvent was distilled off at 100° C.in an oil bath under atmospheric pressure to obtain the residue, whichwas allowed to stand overnight. The temperature of this residue wasreturned to room temperature and ice was added by portions, then 200 mlof methylene chloride were added further to extract and separate theorganic layer. The aqueous layer was made to be pH of 12 or higher with2N potassium hydroxide, which was extracted with methylene chloride (100ml×2). These methylene chloride layers were combined with previouslyextracted layer, dried over anhydrous sodium sulfate, and then solventwas distilled off under reduced pressure to obtain a brown oil. This waspurified by column chromatography (silica gel., ethyl acetate) and thenrecrystallized to obtain 1.94 g (yield 60 %) of title compound.

m.p. 131°-132° C. (2-propanol) colorless needles α!_(D) ³⁰ =+14° (1-50,c. 3.2, chloroform) Elemental analysis (%); As C₂₃ H₂₉ N₃ O₃ Calculated;C: 69.85 H: 7.39 N: 10.62 Found; C: 69.66 H: 7.58 N: 10.56

The starting material,(R)-N-3,4-dimethoxyphenyl-N'-3-(1-phenylmethyl)piperidylethylenediaminewas synthesized similarly to Referential example 1 and Referentialexample 2.

(EXAMPLE 4) (R)-1-(4-fluorophenyl)-3- 3-1-(4-chlorophenylmethyl)!-peperidyl!-2-imidazolidinone

To a 20 ml dried acetonitrile solution of 0.55 g (2.09 mmol) of(R)-1-(4-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone in a 50 mlround-bottomed flask were added 0.31 g (1.07 eg.) of potassium carbonateand 0.45 g (1.05 of 4-chlorobenzyl bromide in turn at room temperatureunder stirring, and the mixture was refluxed for 3 hours. Thereafter,methylene chloride was added to the reaction mixture, the inorganicswere collected by filtration, and the filtrate was distilled off underreduced pressure. The residue obtained was dissolved into methylenechloride, washed with saturated solution of sodium hydrogencarbonate,and the extracted organic layer was dried over anhydrous sodium sulfate.Solvent was distilled off and the residue thus obtained wasrecrystallized to obtain 0.55 g (yield 68 %) of title compound.

m.p. 151°-152° C. (2 - propanol) pale yellow needls α!_(D) ³¹ =-2.0°(1-50, c. 2.3, chloroform) Elemental analysis (%); As C₂₁ H₂₃ ClFN₃ OCalculated; C: 65.03 H: 5.98 N: 10.83 Found; C: 64.91 H: 6.05 N: 10.68

(EXAMPLE 5) (R)-1-(4-fluorophenyl)-3- 3-1-(2-fluorophenylmethyl)!-piperidyl!-2-imidazolidinone

A mixture of 0.50 g (1.90 mmol) of(R)-1-(4-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone, 0.28 g (1.02eg.) of o-fluorophenylbenzyl chloride, 0.29 g (1.51 eg.) oftriethylamine and 10 ml of ethanol in a 200 ml round-bottomed flask wasrefluxed for 1.75 hours. Thereafter, the reaction mixture was distiliedoff under reduced pressure, water was poured to the residue, and it wasmade alkaline with aqueous ammonia, which was extracted with ethylacetate. The extracted organic layers were combined and dried overanhydrous sodium sulfate. Solvent was distilled off under reducedpressure and the residue thus obtained was purified by columnchromatography (silica gel, ethyl acetate:n-hexane 2:1), thenrecrystallized to obtain 0.45 g (yield 64 %) of title compound.

m.p. 96°-97° C. (ethyl acetate: n-hexane) white plates α!_(D) ²⁷ =+20°(1=50, e. 2.1 chloroform) Elemental analysis (%); As C₂₁ H₂₃ F₃ N₃ OCalculated; C: 67.91 H: 6.24 N: 11.31 Found; C: 67.88 H: 6.43 N: 11.32

(EXAMPLE 6) (R)-1-(4-fluorophenyl)-3- 3-1-(3,4-methylenedioxyphenylmethyl!piperidyl!-2-imidazolidinone

To 0.35 g (1.10 eg.) of 3,4-methylenedioxybenzyl alcohol in a 50 mlround-bottomed flask were added 1.68 ml (11 eg.) of thionyl chloride byportions at room temperature, and the mixture was reacted for 3 hours atroom temperature as it is. Carbon tetrachloride was added to thereaction mixture and distilled off under reduced pressure. Then, theresidue was treated azeotropically again with carbon tetrachloride andtoluene. The residue obtained was dissolved into 20 ml of driedacetonitrile at room temperature and, after added 0.55 g (2.09 mmol) of(R)-1-(4-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone and 0.31 g(1.07 eg.) of potassium carbonate in turn to this, the mixture wasrefluxed for 2 hours. Thereafter, the reaction mixture was poured intowater, which was extracted with ethyl acetate. The extracted organiclayers were combined and dried over anhydrous sodium sulfate. Then,solvent was distilled off under reduced pressure and the residue thusobtained was recrystallized to obtain 0.30 g (yield 36 %) of titlecompound.

m.p. 155°-156° C. (acetonitrile) colorless prisms α!_(D) ³⁰ =-1.5° (1=50c. 2.6 chloroform) Elemental analysis (%), As C₂₂ H₂₄ FN₃ O₃ Calculated;C: 66.48 H: 6.09 N: 10.57 Found; C: 66.43 H: 6.19 N: 10.73

(EXAMPLE 7) (R)-1-(4-fluorophenyl)-3- 3-1-(2-methoxyphenylmethyl)!-piperidyl!-2-imidazolidinone

To 0.26 g (0.99 eg.) of 2-methoxybenzyl alcohol in a 200 mlround-bottomed flask were added 2.00 ml (excess amount) of thionylchloride by portions at room temperature, and, after reacted the mixturefor 1 hour at room temperature as it is, the reaction mixture wasdistilled off under reduced pressure.

To the residue obtained were added 10 ml of ethanol, 0.50 g (1.90 mmol)of (R)-1-(4-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone and 0.29 g(1.51 eg.) of triethylamine in turn at room temperature, and the mixturewas refluxed for 4 hours. Thereafter, the reaction mixture was distilledoff under reduced pressure, water was poured to the residue, and it wasmade alkaline with aqueous ammonia, which was extracted with ethylacetate. The extracted organic layers were combined and dried overanhydrous sodium sulfate. Solvent was distilled off under reducedpressure and the residue thus obtained was purified by columnchromatography (silica gel, ethyl acetate), then distilled under reducedpressure to obtain 0.11 g (yield 35%) of title compound.

b.p. 310° C./0.8 mmHg Yellow oil α!_(D) ²² =+23° (1=50, c. 1.1,chloroform) Elemental analysis (%); As C₂₂ H₂₆ FN₃ O₂ Calculated; C:68.91 H: 6.83 N: 10.96 Found; C: 68.72 H: 6.86 N: 10.98

The starting material,(R)-1-(4-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone was synthesizedas follows:

(Referential Example 10)(R)-1-(4-fluorohenyl)-3-(3-piperidyl)-2-imidazolidinone

To a 150 ml methanol solution of 5.50 g (15.6 mmol) of(R)-1-(4-fluorophenyl)-3- 3-(1-phenylmethyl)piperidyl!-2-imidazolidinone(Example 1) in a 300 ml round-bottomed flask were added 1.96 g (2 eg.)of ammonium formate and a 30 ml aqueous suspension of 0.83 g (15 %amounts) of 10 % Pd-C were added in turn at room temperature, and thisreaction mixture was refluxed for 4 hours. The temperature of reactionmixture was cooled to room temperature, catalyst was collected byfiltration, and the filtrate was distilled off under reduced pressure.The residue thus obtained was recrystallized to obtain 2.23 g (yield 54%) of title compound.

m.p. 167°-168° C. (acetonitrile) colorless prisms Ε!_(D) ²⁴ =+13 °(1=50, c. 5.5, chloroform) Elemental analysis; As C₁₄ H₁₈ FN₃ O 0.2H₂ OCalculated; C: 63.00 H: 6.95 N: 15.74 Found; C: 62.92 H: 6.85 N: 15.86

(EXAMPLES 8 THROUGH 27)

Following compounds were synthesized by the similar methods to Examples4 through 7, using(R)-1-(r-fluorophenyl)-3-(3-piperidyl)-2-imidazolidinone (Referentialexample 10) as a starting material. ##STR19##

                                      TABLE 1                                     __________________________________________________________________________                             Specific                                                               Melting point                                                                        rotation**                                                             (Solvent for                                                                         (c. concen-                                                            recrystal-                                                                           tration,                                                                             Elemental analysis (%)                        Example                                                                            R            lization)                                                                            solvent)                                                                             calculated/Found                              __________________________________________________________________________     8                                                                                              96-97° C. (n-Hexane: AcOEt)                                                    α!.sub.D.sup.27 = +6.3° (c.2.2,                                 CHCl.sub.3)                                                                          C.sub.21 H.sub.21 F.sub.2 N.sub.3 O C:                                        67.91 H: 6.24 N: 11.31 C: 67.86 H: 6.29                                       N: 11.30                                       9                                                                                  ##STR20##   105-106° C. (n-Hexane: AcOEt)                                                  α!.sub.D.sup.27 = +7.0° (c.2.3,                                 CHCl.sub.3)                                                                          C.sub.21 H.sub.21 F.sub.2 N.sub.3 O C:                                        67.91 H: 6.24 N: 11.31 C: 68.19 H: 6.14                                       N: 11.23                                      10                                                                                  ##STR21##   115-117° C. (n-Hexane: AcOEt)                                                  α!.sub.D.sup.27 = +8.0° (c.2.6,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.26 FN.sub.3 O C: 71.91 H:                                      7.13 N: 11.44 C: 71.87 H: 7.38 N: 11.30       11                                                                                  ##STR22##   95° C. (n-Hexane: AcOEt)                                                       α!.sub.D.sup.27 = +8.5° (c.2.0,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.26 FN.sub.3 O C: 71.91 H:                                      7.13 N: 11.44 C: 72.02 H: 7.26 N: 11.39       12                                                                                  ##STR23##   162-163° C. (n-Hexane: AcOEt)                                                  α!.sub.D.sup.27 = +7.9° (c.2.2,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.26 FN.sub.3 O C: 71.91 H:                                      7.13 N: 11.44 C: 72.06 H: 7.25 N: 11.40       13                                                                                  ##STR24##   119-121° C. (n-Hexane: AcOEt)                                                  α!.sub.D.sup.27 = -23° (c.2.6,                                  CHCl.sub.3)                                                                          C.sub.21 H.sub.23 FN.sub.4 O.sub.3 C:                                         63.31 H: 5.82 N: 14.06 C: 63.30 H: 5.90                                       N: 14.07                                      14                                                                                  ##STR25##   141-142° C. (n-Hexane: AcOEt)                                                  α!.sub.D.sup.27 = +4.3° (c.2.1,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.26 FN.sub.3 O.sub.2 C:                                         68.91 H: 6.83 N: 10.96 C: 68.77 H: 6.97                                       N: 10.88                                      15                                                                                  ##STR26##   168° C. (n-Hexane: AcOEt)                                                      α!.sub.D.sup.27 = +4.7° (c.2.1,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.23 F.sub.4 N.sub.3 O C:                                        62.70 H: 5.50 N: 9.97 C: 63.06 H: 5.48 N:                                     9.98                                          __________________________________________________________________________     **1 = 50                                                                 

                                      TABLE 2                                     __________________________________________________________________________                                Specific                                                               Melting point                                                                        rotation**                                                             (Solvent for                                                                         (c. concen-                                                            recrystal-                                                                           tration,                                                                             Elemental analysis (%)                     Example                                                                            R               lization)                                                                            solvent)                                                                             calculated/Found                           __________________________________________________________________________    16                                                                                  ##STR27##      137-138° C. (iso-Pr.sub.2  O)                                                  α!.sub.D.sup.28 = +3.7° (c.2.9,                                 CHCl.sub.3)                                                                          C.sub.23 H.sub.26 FN.sub.3 O C: 71.91                                         H: 7.13 N: 11.44 C: 71.73 H: 7.26 N:                                          11.41                                      17                                                                                  ##STR28##      180-181° C. (CH, CN)                                                           α!.sub.D.sup.31 = -5.4° (c.2.8,                                 CHCl.sub.3)                                                                          C.sub.21 H.sub.27 BrFN.sub.3 O C:                                             58.34 H: 5.36 N: 9.72 C: 58.17 H: 5.42                                        N: 9.73                                    18                                                                                  ##STR29##      115-116° C. (2-PrOH: iso-Pr.sub.2 O)                                           α!.sub.D.sup.30 = -20° (c.2.5,                                  CHCl.sub.3)                                                                          C.sub.22 H.sub.23 FN.sub.4 O C: 69.82                                         H: 6.13 N: 14.80 C: 70.02 H: 6.14 N:                                          14.77                                      19                                                                                  ##STR30##      113-114° C. (n-Hexane)                                                         α!.sub.D.sup.30 = +2.4° (c.2.3,                                 CHCl.sub.3)                                                                          C.sub.25 H.sub.32 FN.sub.3 O C: 73.32                                         H: 7.88 N: 10.26 C: 73.35 H: 7.91 N:                                          10.13                                      20                                                                                  ##STR31##      136-137° C. (CH, CN)                                                           α!.sub.D.sup.30 = -13° (c.1.6,                                  CHCl.sub.3)                                                                          C.sub.22 H.sub.28 FN.sub.3 O C: 75.50                                         H: 6.57 N: 9.78 C: 75.61 H: 6.72 N:                                           9.79                                       21                                                                                  ##STR32##      138-139° C. (CH.sub.3 CN˜ 2-PrOH)                                        α!.sub.D.sup.28 = +4.5° (c.2.3,                                 CHCl.sub.3)                                                                          C.sub.23 H.sub.28 FN.sub.3 O.sub.2 C:                                         69.50 H: 7.10 N: 10.57 C: 69.41 H:                                            7.25 N: 10.45                              22                                                                                  ##STR33##      103-104° C. (n-Hexane)                                                         α!.sub.D.sup.31 = +3.5° (c.2.4,                                 CHCl.sub.3)                                                                          C.sub.24 H.sub.30 FN.sub.3 O C: 72.88                                         H: 7.65 N: 10.62 C: 72.94 H: 7.73 N:                                          10.59                                      23                                                                                  ##STR34##      141-142° C. (2-PrOH)                                                           α!.sub.D.sup.29 = -5.6° (c.2.6,                                 CHCl.sub.3)                                                                          C.sub.22 H.sub.26 FN.sub.3 OS C: 66.14                                        H: 6.56 N: 10.52 C: 66.14 H: 6.83 N:                                          10.50                                      __________________________________________________________________________     **1 = 50                                                                 

                                      TABLE 3                                     __________________________________________________________________________                             Specific                                                               Melting point                                                                        rotation**                                                             (Solvent for                                                                         (c. concen-                                                            recrystal-                                                                           tration,                                                                             Elemental analysis (%)                        Example                                                                            R            lization)                                                                            solvent)                                                                             calculated/Found                              __________________________________________________________________________    24                                                                                  ##STR35##   136-137° C. (2-PrOH)                                                           α!.sub.D.sup.29 = +5.8° (c.1.8,                                 CHCl.sub.3)                                                                          C.sub.23 H.sub.28 FN.sub.3 O C: 72.41 H:                                      7.40 N: 11.01 C: 72.36 H: 7.64 N: 11.00       25                                                                                  ##STR36##   150-151° C. (2-PrOH)                                                           α!.sub.D.sup.28 = +5.4° (c.2.2,                                 CHCl.sub.3)                                                                          C.sub.23 H.sub.28 FN.sub.3 O C: 72.41 H:                                      7.40 N: 11.01 C: 72.33 H: 7.31 N: 10.96       26                                                                                  ##STR37##   106-107° C. (n-Hexane)                                                         α!.sub.D.sup.31 = +6.6 ° (c.2.5,                                CHCl.sub.3)                                                                          C.sub.23 H.sub.28 FN.sub.3 O C: 72.41 H:                                      7.40 N: 11.01 C: 72.32 H: 7.43 N: 10.95       27                                                                                  ##STR38##   247-249° C. (CH.sub.3 CN)                                                      α!.sub.D.sup.30 = +51° (c.1.9,                                  CHCl.sub.3)                                                                          C.sub.25 H.sub.32 FN.sub.3 O HCl                                              0.2H.sub.2 O C: 66.79 H: 7.49 N: 9.35 C:                                      66.94 H: 7.66 N: 9.35                         __________________________________________________________________________     *HCl salt                                                                     **1 = 50                                                                 

(EXAMPLE 28) (R)-1-(2-fluorophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

To 0.76 g (1.9.7 mmol) of(R)-N-3-(1-phenylmethyl)-piperidyl-N-(2-methoxyethyl)-N'-2-fluorophenylureawere added dropwise 20 ml of 48 % hydrobromic acid under stirring andcooling with ice, and then the mixture was refluxed for 8 hours. Thereaction mixture was poured into ice water and potassium hydroxide wasadded to this under cooling with ice to make pH 12 or higher, which wasextracted thrice with 20 ml of methylene chloride. The extractedsolutions were combined and dried over anhydrous sodium sulfate. Then,solvent was distilled off under reduced pressure and the residue thusobtained was purified by column chromatography (alumina, ethylacetate:nhexane=1:1). It was then crystallized at 5° C. andrecrystallized to obtain 0.37 g (yield 53 %) of title compound.

m.p. 90°-92° C. (n-hexane) colorless powders α!_(D) ²⁵ =+9.8° (1=50, c.1.0, hloroform) Elemental analysis (%); As C₂₁ H₂₄ FN₃ O Calculated; C:71.36 H: 6.84 N: 11.89 Found; C: 71.21 H: 6.84 N: 12.03

The starting material,(R)-N-3-(1-phenylmethyl)piperidyl-N-(2-methoxyethyl)-N'-2-fluorophenylureawas synthesized as follows:

(Referential Example 11)(R)-3-(methoxyacetylamino)-1-phenylmethylpiperidine

To a 50 ml anhydrous tetrahydrofuran solution of 5.00 g (26.3 mmol) of(R)-1-phenylmethyl-3-aminopiperidine (Referential example 7) in a 300 mlthree-necked flask was added a 50 ml anhydrous tetrahydrofuran solutionof 3.20 g (1.2 eg.) of triethylamine, and, to this reaction mixture wasadded dropwise a 50 ml anhydrous tetrahydrofuran solution of 2.85 g (1.0eg.) of methoxyacetyl chloride under stirring and cooling with ice.After reacted for 5 hours at room temperature, methylene chloride andsmall amount of water were added to extract (20 ml×6). The organiclayers were combined and dried over anhydrous sodium sulfate. Then,solvent was distilled off under reduced pressure and the residue thusobtained was purified by column chromatography (alumina, ethylacetate:n-hexane=1:1) to obtain 6.67 g (yield 97 %) of title compound asa pale yellow oil.

α!_(D) ²⁰ =+6.4° (1=50, c. 2.0, ethanol) MASS; As C₁₅ H₂₂ N₂ O₂ m/e; 262(M⁺, base) 217, 173

(Referential Example 12)(R)-3-(2-methoxyethylamino)-1-phenylmethylpiperidine

To a 50 ml anhydrous tetrahydrofuran suspension of 0.87 g (2.0 eg.) oflithium aluminum hydride in a 300 ml round-bottomed flask was addeddropwise a 20 ml anhydrous tetrahydrofuran solution of 3.00 g (11.4mmol) of (R)-3-(2-methoxyacetylamino)-1-phenylmethylpiperidine. Afterstirred for 1 hour at room temperature, the reaction mixture wasrefluxed for 3 hours. Further, 0.87 g (2.0 eg.) of lithium aluminumhydride were added and the mixture was refluxed for 3 hours. Thereaction mixture was stirred under cooling with ice and, after added 180ml of ethyl acetate and a 10 ml aqueous solution of sodium hydroxide(1.82 g, 4.0 eg.) in turn to this and stirred for 30 minutes, anhydrousmagnesium sulfate was added and it was filtered with celite. Thefiltrate was distilled off under reduced pressure and the residue thusobtained was purified by column chromatography (alumina, ethylacetate:n-hexane=1:2) to obtain 2.03 g (yield 72 %) of title compound asa brown oil.

α!_(D) ²⁵ =-10° (1=50, c. 1.0, ethyl acetate) MASS; As C₁₅ H₂₄ N₂ O m/e;248 (M⁺), 216, 173, 147 (base), 134

(Referential Example 13)(R)-N-3-(1-phenylmethyl)piperidyl-N-(2-methoxyethyl)-N'-2-fluorophenylurea

To a 20 ml dried methylene chloride solution of 1.00 g (4.03 mmol) of(R)-3-(2-methoxyethylamino)-1-phenylmethylpiperidine in a 100 mlround-bottomed flask was added dropwise a solution of 0.55 g (1.0 eg.)of 2-fluorophenylisocyanate in methylene chloride 5 ml under stirringand cooling with ice. After stirred the reaction mixture for 8 hours atroom temperature, solvent was distilled off under reduced pressure andthe residue obtained was dissolved into 30 ml of methylene chloride,which was extracted with 20 ml of 3N hydrochloric acid (×4).This-hydrochloric acid layer was made to be pH of 12 or higher withdiluted aqueous solution of potassium hydroxide under cooling with ice.This was extracted with 20 ml of methylene chloride (×4), then driedover anhydrous sodium sulfate, and solvent was distilled off underreduced pressure. The residue thus obtained was purified by columnchromatography (ethyl acetate:n-hexane=1:2) to obtain 0.85 g (yield 55%) of title compound as a pale yellow oil.

α!_(D) ²³ =+15° (1=50, c. 1.2, ethyl acetate) MASS; As C₂₂ H₂₈ FN₃ O₂m/e; 385 (M⁺), 354, 248, 174 (base), 134

(EXAMPLE 29) (R)-1-(3-fluorophenyl)-3-3-(1-phenylmethyl)piperidyl!-2-imidazolidinone

Using(R)-N-3-(1-phenylmethyl)piperidyl-N-(2-methoxyethyl)-N'-3-fluorophenylurea,title compound was synthesized similarly to Example 28.

m.p. 84°-86° C. (n-hexane) colorless needles α!_(D) ²⁶ =11° (1=50, c.1.0, chloroform) Elemental analysis (%); As C₂₁ H₂₄ FN₃ O Calculated; C:71.36 H: 6.84 N: 11.89 Found; C: 71.25 H: 6.96 N: 11.67

The starting material,(R)-N-3-(1-phenylmethyl)piperidyl-N-(2-methoxyethyl)-N'-3-fluorophenylureawas synthesized similarly to Referential example 13, using(R)-3-(2-methoxyethylamino)-1-phenylmethylpiperidine (Referentialexample 12) and 3-fluorophenylisocyanic acid.

(Referential Example 14)(R)-N-3-(1-phenylmethyl)piperidyl-N-(2-methoxyethyl)-N'-3-fluorophenylurea

m.p. 91°-94° C. (n-hexane) colorless powders α!_(D) ²² =+17° (1=50, c.1.0, ethyl acetate) MASS; As C₂₂ H₂₈ FN₃ O₂ m/e; 385 (M⁺), 354, 173,147, 91 (base)

(Experimental Example 1)

In Vitro Biochemical Test

1) Radioligand binding experiment to M₁ type muscarinic cholinergicreceptor

Method: To a crude synaptic membrane specimen prepared from all brains(except cerebellum and brain stem) of rat, ³ H!-pirenzepine ( ³ H!-PZ,final oncentration: 1 nM) and testing compound were added and themixture was incubated for 60 minutes at 25 ° C. After stopped thereaction by high-speed suction filtration, the radioactivity on filterwas measured with liquid scintillation counter. The specific bindinglevel of ³ H!-pirenzepine was determined by subtracting the nonspecificbinding level in the presence of atropine (1 μM) from total bindinglevel. Putting the ³ H!-pirenzepine binding in the absence of testingcompound on 100, the concentration of compound to decrease by 50 % (IC₅₀value) was made an index of the binding activity of compound to M₁muscarinic receptor (refer to: J. A. D. M. Toner et al, Life Science,1987, 40, 1981-1987).

2) Radiolignd binding experiment to M₂ type muscarinic cholinergicrecetor

Method: Similar procedures were conducted to the experiment on theaffinity to M₁ receptor, except that the crude synaptic membranespecimen was prepared from the brain stem (medulla oblongata-pons) ofrat and ³ H!-quinuclidyl benzoate ( ³ H!-QNB, 0.1 nM) was used as aradioactive ligand.

3) Selectivity to M₁ receptor

This was determined from the ratio of IC₅₀ values of compound obtainedfrom the binding experiments of M₁ and M₂ muscarinic receptors. ##EQU1##

                  TABLE 4                                                         ______________________________________                                        No. of    .sup.3 H!-PZ (M.sub.1)                                                                   .sup.3 H!-QNB (M.sub.2)                                  compound IC.sub.50 μM                                                                          IC.sub.50 μM                                                                           IC.sub.50 (M.sub.2)/IC.sub.50                 ______________________________________                                                                        (M.sub.1)                                     Example 1                                                                              0.03       0.5         16.7                                          Referential                                                                            0.08       1.09        13.6                                          example 8                                                                     Referential                                                                            3.7        >10.0       >2.7                                          example 9                                                                     ______________________________________                                    

Results: Table 4 shows the affinity and selectivity of the inventivecompound to M₁ and M₂ receptors. IC₅₀ value of ³ H!-PZ denotes theaffinity to M₁ receptor and IC₅₀ value of ³ H!-QNB the affinity to M₂receptor. It is shown that the higher the ratio of M₂ /M₁, the higherthe selectivity to M₁ receptor.

The reusults show that the inventive compound has patent affinity to thecentral M₁ muscarinic receptor and that it has far higher selectivity toM₁ receptor than to M₂ receptor. Besides, in the affinity to receptors,the compound of the invention (R isomer) is about 3 times more excellentthan that of Referential example 8 (racemic form) and about 120 timesmore excellent than that of Referential example 9 (S isomer).

(Experimental Example 2)

In vivo pharmacological test

Testing on the pirenzepine-induced amnesia

For the experiment animals, Std:ddY strain male mice with body weight of24 to 34 g (age in week: 5-6) (Nippon SLC) were used. For the device, astep-through type passive avoidance apparatus (made by Ohara MedicalCo., Ltd.) consisting of two tight and dark rooms was used. In theacquisition trial, mouse was placed in the light room and, 10 secondslater, the partitive guillotine door was opened. As soon as the mousemoved into the dark room, the guillotine door was closed and electricshock of 41 to 45 V was given for 1 second through the metal grid barsof the floor. The retention trial was conducted 24 hours later sincethen. In the retention trial, mouse was placed again in the light roomand the time until they moved into the dark room was measured for atmaximum 300 seconds as a reaction latency; for mouse exhibited longerlatency than those, the time was made to be 300 seconds. The inductionof amnesia was performed by fixing a mouse at prone position withoutanesthetization at 20 minutes before learning acquisition trial andinjecting pirenzepine (10 μg/2 μl/mouse bilaterally into cerebralventricles using a microsyringe. Moreover, a group not to administeredwith pirenzepine before acquisition trial (non-amnesia comparison group)was also provided. The mice were made to be 12 to 21 animals per groupand the testing compound was administered orally at 30 or 60 minutesbefore acquisition trial. The improvement rate was calculate accordingto following equation and the results are shown in Table 5 (refer to: M.P. Callfield et at, J. Pharm. Pharmacol. 1983, 35, 131-132). ##EQU2##

                  TABLE 5                                                         ______________________________________                                                             Number           Improve-                                              Dose   of      Reaction ment                                                  (mg/   animals latency  rate                                    Compound      kg)    used    Mean ± S.E.                                                                         (%)                                     ______________________________________                                        Non-treated   --     13      154.0 ± 29.7##                                Pirenzepine - treated mouse                                                                 --     13      58.8 ± 27.1                                   Example 1      3     13      91.5 ± 21.4                                                                         34.3                                                  10     13      133.0 ± 29.3#                                                                       77.9                                                  30     12      166.9 ± 40.2#                                                                       113.6                                   Non-treated   --     21      276.0 ± 12.9##                                Pirenzepine - treated mouse                                                                 --     21      93.0 ± 26.1                                   Referential example 8                                                                        3     21      55.1 ± 20.0                                                                         -20.7                                                 10     21      153.7 ± 27.6#                                                                       33.2                                    Non-treated   --     12      211.6 ± 26.2#                                 Pirenzepine - treated mouse                                                                 --     12      91.5 ± 30.3                                   Referential example 9                                                                        3     12      63.3 ± 32.1                                                                         -23.5                                                 10     12      61.5 ± 26.5                                                                         -25.0                                                 30     13      113.2 ± 36.2                                                                        18.1                                    ______________________________________                                         *: p < 0.05 ##: p < 0.01 With significant difference against                  pyrenezepinetreated mice                                                 

Results: Table 5 shows the improvement effect of the inventive compoundon the pirenzepine-induced amnesia.

The reduction of the reaction latency of pirenzepine-treated micerelative to the group without treatment indicates that the decreasedlearning effect due to electric shock, that is, amnesia is caused. Theextension of the reaction latency with compound therefore means theimproved amnesia.

The results show that the inventive compound (R isomer) and the compoundof Referential example 8 (racemic form) have very excellent improvementeffect on the amnesia caused by the disturbance of central cholinergicnerves. On the contrary, the compound of Referential example 9 (Sisomer) could not improve the amnesia induced with pyrenezepine.

(Experimental Example 3)

In Vivo Toxicity Test

For the experiment animals, 4 animals per group of Std:ddY strain malemice with body weightOf 26 to 30 g (age in week: 5) (Nippon SLC) wereused. The testing compound was suspended into 5 % solution of arabic gumand administered orally. The common symptoms and death caused withcompound were recorded for 3 days after administration.

                  TABLE 6                                                         ______________________________________                                                  Dose (mg/kg)                                                        No. of compound                                                                              300       600       1200                                       ______________________________________                                        Example 1      None      None      None                                       Referential    None      Convul-   Death 4/4                                  example 8                sion 3/4                                             Referential    Convul-   Death 4/4 --                                         example 9      sion 2/4                                                                      Death 1/4                                                      ______________________________________                                    

Results: Table 6 shows the common symptoms and death appearing at thetime of administering the inventive compound.

With the compound of Referential example 8 (racemic form), theconvulsion was observed at 600 mg/kg and the death of 1200 mg/kg, and,with the compound of Referential example 9 (S isomer), both convulsionand death were observed at the administration of 300 mg/kg or more.Whereas, with the compound of the invention, such symptom was not causedeven at 1200 mg/kg. It was suggested that the toxic action exhibitedwith racemic form depended on the S isomer.

Utilizability in the Industry

As described above, the optically active imidazolidinone derivatives ortheir acid adducts with functionally cholinergic activity (muscarine M₁activity) are useful as therapeutic drugs of senile dementia.

We claim:
 1. A stereoisomer 3-(R)-imidazolidinonyl piperidine of thefollowing structure: ##STR39## (wherein R and R¹ denote identically ordifferently hydrogen atoms, halogen atoms, lower alkyl groups which maybe substituted by halogen atoms, lower alkoxy groups, lower alkylthiogroups, lower alkoxycarbonyl groups, nitro groups, amino groups or cyanogroups, and n denotes 1 to 4), or an acid addition salt.
 2. Thestereoisomer of claim 1, wherein R is a hydrogen atom, R¹ is any ofhalogen atom, lower alkyl group which may be substituted by halogen atomand lower alkoxy group, and n is 1, or an acid addition salt.
 3. Thestereoisomer of claim 1, wherein R¹ is a halogen atom, R is any ofhalogen atom, lower alkyl group which may be substituted by halogen atomand lower alkoxy group, and n is 1, or an acid addition salt.
 4. Thestereoisomer of claim 1, wherein the stereoisorner is (R)- 1-(3-fluorophenyl)-3 - 3-(1-phenylmethylpiperidyl)!-2-imidazolidinone. 5.The stereoisomer of claim 1, wherein the stereoisomer is(R)-1-(4-trifluoromethylphenyl)-3-3-(1-phenylmethylpiperidyl)!-2-imidazolidinone.
 6. The stereoisomer ofclaim 1, wherein the stereoisomer is (R)-1-(3-trifluoromethylphenyl)-3-3-(1-phenylmethylpiperidyl)!-2-imidazolidinone.
 7. The stereoisomer ofclaim 1 having the following formula: ##STR40##
 8. The stereoisomer ofclaim 1 having the following formula: ##STR41##
 9. The composition ofclaim 8, wherein the stereoisomer has the following formula: ##STR42##10. The composition of claim 8, wherein the stereoisomer has thefollowing formula: ##STR43##
 11. A pharmaceutical composition comprisinga therapeutically effective amount of a stereoisomer3-(R)-imidazolidinonyl piperidine of the following structure: ##STR44##(wherein R and R¹ denote identically or differently hydrogen atoms,halogen atoms, lower alkyl groups which may be substituted by halogenatoms, lower alkoxy groups, lower alkylthio groups, lower alkoxycarbonylgroups, nitro groups, amino groups or cyano groups, and n denotes 1 to4), or an acid addition salt, and a pharmaceutically acceptable carrier.